Our story

February 2014
(2016 update and preliminary results of the Curcumin Genistein trial at the bottom of this page!)

WE DID IT!!!!

WE FOUND IT!!!

I CAN'T BELIEVE IT!!!

The latest sweat test came back at 59mmol/L!! We're below the magic 60!

How the sweat test is used for diagnosis of CF:
less than 40 = no CF
between 40 and 60 = inconclusive
more than 60 = CF

Our sweat test history:
at diagnosis in Nov 2008: 118mmol/L
May 2013: 90mmol/L
Feb 2014: 59mmol/L

Since May 2013 we have changed nothing except gone up on the dose of Curcumin and Genistein.

IT WORKS!!!

IT REALLY REALLY WORKS!!!

For our friends that don't know much about CF, this means that the cells that were not working because of CF, are now working. Not all the way (yet), but almost as good as in non-CF people. This means his lungs (and other organs affected by CF, like the intestines, liver and pancreas) are working a lot better than before. J is not 'cured', as CF is caused by gene mutations in DNA. The cells affected by CF regenerate every 48 hours, so the body keeps making faulty cells continuously. But as long as he takes these supplements every day, the underlying cell defect that causes the symptoms (and mortality) in CF is (almost) repaired.

We were using 3600mg of Curcumin with piperine and 150mg Genistein per day, dissolved in hot soy milk, for a weight of 44kg in at the time of the sweat test in February 2014. We spread this out into 4 doses throughout the day, taken with fatty foods and enzymes.

Some might think a drop in sweat chloride levels could be a coincidence or something that can happen spontaneously. It doesn't. I did not pay attention in Statistics class on how to calculate the chance that this is a coincidence, but if I'd had to guess it would be p=0.000andalotmorezeros1. This doesn't just 'happen' in CF. Below are some graphs from scientific research articles on the new medication (Kalydeco/VX770)) for CF that corrects the underlying defect. You'll see that the drop in sweat chloride we have found (minus 59mmol/L) is even greater than what is seen on 150mg of Kalydeco. (please note that the drop from 118 to 59, is coincidentally the same as the absolute result of the sweat test, which is also 59)

It might be interesting to know that the price for Kalydeco (=VX770) is over $300,000 per patient per year. What we use now costs a little over $2,000 per year. That is 0.7% or the price of Kalydeco!

I will write a page on what we do exactly, what else we give and how we give it, but for now, I really wanted to let you know these results!

It is uncertain which mutations can benefit from the combination of Curcumin and Genistein. At first I thought it would only work for gating mutations (Class 3, see the story below), but there have been some people with double delF508 that have started trying at low doses and have noticed the exact same results as we did in the beginning. So it's definitely worth a try!

If anyone has tried, or is going to try these supplements, I would love to hear from you! Please send me an e-mail at curcumingenistein@yahoo.com


This is how I started this blog in October 2013:
(Before you begin to read the rest, please note I am a CF mom, not a doctor. There is no proof, other than ‘in vitro’ and ‘ex vivo’ tests (and now the sweat chloride test!), that the combination of supplements mentioned below works for people with CF. We think it does, but we are not sure (latest update from users, see 'Early Results'). There is no safety information. We don’t know if this combination is safe for people with CF. There is a lot of information on the use of each supplement separately. They both have a very good safety profile. Even high doses have been used short term without apparent problems. But that is not the same thing as combining the two in a CF patient. I am not recommending the use of these supplements in doses higher than the daily recommended dose by the manufacturer, it may work better in higher doses, but I don’t want to harm anyone with my recommendations……. It’s completely up to you if you want to try. But please be careful! Safety first!)

Our story:

Our son J was born in 2006 and was diagnosed in 2008 with Cystic Fibrosis (S1251N, a so called ‘gating’ mutation and delF508). I soon started researching everything to do with CF, every chance I got, hoping to find something to keep my son as healthy as possible. Slowly we added more and more supplements to his daily routine, based on what I learned.

J is now (2013) seven years old (2016 update is at the bottom of this page) and has stayed super healthy over the last 5 years. His health has actually improved. His lung CT scans are now 100% okay, he has been able to eradicate Pseudomonas after culturing it for a year and half, his liver enzyme levels have returned to normal, so he no longer needs Urso. We were even able to lower his enzyme use to about half of what it was before (he now uses one Creon10 for 20 grams of fat). He shows no symptoms of CF, expect for (partial?) pancreatic insufficiency and a sweat chloride level of still 90 mmol/L (he had 118 mmol/L at diagnosis, so his sweat chloride has dropped 28 mmol/L, but is still very much in the ‘CF range’). He is also ‘off the charts’ overweight (oops…, but hey…they said give him lots of fat, didn’t they?) and his height is well above average for his age. Besides vitamins and supplements he uses no medication other than Creon, some allergy medication and some Macrogol to help keep his stools soft.

The truth is, we didn’t know exactly which of the supplements was doing the trick or if it was a combination of different things. So this year an opportunity presented itself to test some of the supplements on his own (intestinal) cells (‘ex vivo’) and we found what is probably the biggest reason he is doing so well….

It’s the combination of Curcumin and Genistein. They have a synergistic effect. Used together in relatively low concentrations they potentiate his CFTR function substantially (‘ex vivo’ that is).

Would one use only Curcumin or only Genistein in low concentrations, it would probably not make a noticeable difference on CFTR function. However, combine them in the human body and BOOM! It works! Like a magic factory!

There are two research articles that I know of, referring to the additive and/or synergistic effect of Curcumin and Genistein on CFTR.

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First:

J Cyst Fibros. 2011 Jul;10(4):243-52. doi: 10.1016/j.jcf.2011.03.001. Epub 2011 Mar 26.

Curcumin and genistein additively potentiate G551D-CFTR.

Yu YC, Miki H, Nakamura Y, Hanyuda A, Matsuzaki Y, Abe Y, Yasui M, Tanaka K, Hwang TC, Bompadre SG, Sohma Y.

Source

Department of Pharmacology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan.

Abstract

BACKGROUND:

The G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) is a common cause of cystic fibrosis (CF). G551D-CFTR is characterized by an extremely low open probability despite its normal trafficking to the plasma membrane. Numerous small molecules have been shown to increase the activity of G551D-CFTR presumably by binding to the CFTR protein.

METHODS:

We investigated the effect of curcumin, genistein and their combined application on G551D-CFTR activity using the patch clamp technique.

RESULTS:

Curcumin increased G551D-CFTR whole-cell and single-channel currents less than genistein did at their maximally effective concentrations. However, curcumin further increased the channel activity of G551D-CFTR that had been already maximally potentiated by genistein, up to ~50% of the WT-CFTR level. In addition, the combined application of genistein and curcumin over a lower concentration range synergistically rescued the gating defect of G551D-CFTR.

CONCLUSIONS:

The additive effects between curcumin and genistein not only support the hypothesis that multiple mechanisms are involved in the action of CFTR potentiators, but also pose pharmaceutical implications in the development of drugs for CF pharmacotherapy.

Copyright © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

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Second:

Curr Pharm Des. 2013;19(19):3521-8.

Curcumin and genistein: the combined effects on disease-associated CFTR mutants and their clinical implications.

Sohma Y, Yu YC, Hwang TC.

Department of Pharmacology, Keio University School of Medicine 35 Shinanomachi, Shinjuku, Tokyo, Japan. yoshiros@sc.itc.keio.ac.jp

Abstract

Genistein and curcumin are major components of Asian foods, soybean and curry turmeric respectively. These compounds have been intensively investigated for their chemical and biological features conferring their anti-cancer activity. Genistein and curcumin have also been investigated for their potentiation effects on disease-associated CFTR mutants such as ΔF508 and G551D. Recently, we investigated the combined effect of genistein and curcumin on G551D-CFTR, which exhibits gating defects without abnormalities in protein synthesis or trafficking using the patch-clamp technique. We found that genistein and curcumin showed additive effects on their potentiation of G551D-CFTR in high concentration range and also, more importantly, showed a significant synergistic effect in their minimum concentration ranges. These results are consistent with the idea that multiple mechanisms are involved in the action of these CFTR potentiators. In this review, we revisit the pharmacology of genistein and curcumin on CFTR and also propose new pharmaceutical implications of combined use of these compounds in the development of drugs for CF pharmacotherapy.

PMID: 23331029 [PubMed - in process]

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(unfortunately these articles are copyrighted and I am by law not permitted to place the full text on this blog)

The research from the second article shows that combining Curcumin and Genistein on G551D cells ('in vitro') in low concentrations shows a synergistic effect of restoring the gating defect of G551D-CFTR up to around 50% (!!!!) of normal. The authors conclude: "This combination might succeed in activating the mutant CFTR channel up to a therapeutic level."

The research was done on G551D. My son J has S1251N (a Dutch Class 3 gating mutation). So now we know it works on G551D and S1251N.

I have no information on any other mutations it might work for. Logically one could think the combination might also work on other gating mutations (G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P,  G1349D). One could think residual function mutations like R117H might also benefit or conductance mutations like E56K, P67L, D110E, D110H, R117C, R347H, R352Q, A455E, D579G, S945L, L206W, R1070W, F1074L, D1152H, S1235R, D1270N, 2789+5G->A, 3849+10kbC->T, 3272-26A->G, 711+5G->A, 3120G->A, 1811+1.6kbA->G, 711+3A->G, 1898+3A->G, 1898+1G->A, 1717-1G->A, 1717-8G->A, 1342-2A->C, 405+3A->C, 1716G/A 1811+1G->C, 1898+5G->T, 3850-3T->G, IVS14b+5G->A, 1898+1G->T, 4005+2T->C, 621+3A->G and 621+1G->T.

But as I said, I don’t know. It may work on more mutations….Probably not, but I am not sure.

The mutations mentioned above will probably also benefit from Kalydeco. But for those who don’t have access to Kalydeco (yet), this combination of supplements might be useful in the meantime.

Just using the daily recommended dose of both Curcumin and Genistein, has made a huge difference. Using higher doses could have more effect, but, especially in the long run, also increases the risk of side effects.

BUT….the weird thing is, the research articles above show that at LOW concentrations, the combination works BETTER than at higher concentrations.  The lower the concentration, the better it works. Completely opposite to what is usually seen. However (!), we’re talking laboratory ‘in vitro’ concentrations, which are extremely high compared to what one would be able to accomplish ‘in vivo’. You’d have to take a bathtub full of Curcumin every hour to get to those concentrations in the blood…… The good thing is, the lowest concentration they use in the test, is probably one that CAN be reached ‘in vivo’. BUT…..we don’t know the effect of the combination on CFTR at even lower concentrations, since the researchers didn’t test that, or to be precise no results of a test with lower concentrations are mentioned in the article. Since the dose-response curve is the mirror image of what one usually sees, until further information on the subject is available, we’ll just have to try and figure out the best dose for ourselves.

What it comes down to is this….. ‘in vivo’ we don’t know what doses or concentrations would work best and at which ratio. You can’t even compare ‘in vitro’ concentrations to ‘in vivo’ concentrations since in an ‘in vitro’ setting there is no blood flow to the cell. The cell literally needs to be bathed in the solution to get it into the cell. In the human body there is blood flow to and through the cell. The blood will take the compounds into the cell. So ‘in vivo’ one would need lower concentrations to reach the same effect as ‘in vitro’.

Here at home with J we are trying different doses and closely observing the effects. If we go up or down on the dose of either one of the supplements, we only change 1 of the supplements at the time and only 1 capsule at a time. We take at least two weeks to observe if there is any noticeable improvement or worsening.

J takes the supplements together with fatty foods and enzymes. Curcumin and Genistein are fat soluable. If you don’t take it with fat (and enzymes) it probably won’t be absorped by the intestines at all. He takes it divided over at least 4 doses throughout the day.

Absorption is a problem with Curcumin according to most research (even when you take it with fatty foods). However, even in low doses, we have the healthy living proof of our young hero to show that it works. I don’t know where it goes after ingestion, but for him it works. It gets to the lungs!

On the other hand, maybe we don’t want all of the Curcumin absorbed. We might want to leave some Curcumin in the intestine, so it can do it’s work on the intestinal mucosa from the inside and not through the blood. We have seen effects on J that might point in that direction.

We have noticed that dissolving Curcumin in hot (soy)milk improves absorption. We microwave about 30ml to boiling point, take it out of the microwave, open one Curcumin capsule, poor it into the milk. Stir, strain a few times, and stir some more until all is dissolved, than mix it into 200ml of chocolate milk (hot or cold). If a seven year old drinks it without complaints, it must be palatable for most everyone. Another idea might be dissolving Curcumin in a cup of hot soup. But this pre-dissolving is not necessary. Just taking a little more Curcumin would give you the same added effect.

So by dissolving Curcumin it is absorbed better, which we notice in the lungs (wet cough), not dissolving it seems better for his digestion (firmer stools) though, to be honest, we are not always sure if the changes in stools we see are an improvement or worsening of symptoms…….). I have to try more combinations to see if this is indeed the case.

All in all, it’s completely experimental. Yes, there is scientific evidence it works in a laboratory setting (‘in vitro’) and on living human cells (‘ex vivo’), but we absolutely don’t know what happens in the CF body (‘in vivo’) after taking this combination of supplements.  There is nothing I can say about safety, except for my son taking no more than the daily recommended dose of both supplements (adjusted for his weight) for the last 5 years and noticing no ill effects.

Writing this, I have no idea how many people are going to read this and how many questions will come my way. I hope I will be able to answer them….

The brand we use is AOV for both Curcumin and Genistein (March 2016, we have changed brands due to decreased solubility of the AOV Curcumin. We now use Vitakruid C3-2X, very similar to California Gold Nutrition Curcumin with Bioperine from i-herb. See 'how to start' page). AOV is a Dutch brand (from The Netherlands, that is). It’s Curcumin with added Bioperine (piperine) with a daily recommended dose of 1,200mg Curcumin and Genistein Soy Isoflavone Complex with the daily recommended dose of 440mg complex, containing 97mg pure Genistein. The daily recommended dose is for a person weighing around 70kg. We have been using about half that dose for both supplements for years. At this moment (September 2013) we are experimenting with higher doses (2,400mg of Curcumin and 150mg of Genistein for a weight of 42kg), but as I said earlier, I don’t want to recommend it to anyone, since I don’t know if it is safe.

As it looks now, a good ratio for Curcumin (with piperine/Bioperine) to Genistein would be around 20:1. So, for example, if you take 2000mg of Curcumin with piperine, aim for 100mg of genistein. 

We have not established a most effective dose for J yet. We are just trying and observing. We know it’s doing something, but we don’t know if we can get more effect out of it. He still a young child and he can’t tell us much about what he feels in his body. An older CF patient might have a better ‘feel’ for any changes happening in the body. If anyone wants to try other doses, it’s completely up to you. All I can do is share our experience and knowledge in the hope it can help other people with CF stay as healthy as possible.

UPDATE 2016
J is doing wonderfully well, still! In fact he's only gotten healthier over the last year. We started Kalydeco in June of 2015 (see 'Kalydeco' page at the top right hand side of this blog). We've tried Kalydeco by itself for a few months, Kalydeco + Curcumin and Kalydeco + Genistein. To be honest I couldn't tell a difference. So we chose to do Kalydeco + Curcumin + Genistein. In vitro (lab) studies (J. Dekkers et al, Journal of Cystic Fibrosis, 2016 ) showed  that they all work synergistically at potentiating the CFTR gating defect.
The anti-inflammatory effects of Curcumin do feel very important to me. Curcumin is also known to have anti-bacterial, anti-viral, anti-fungal and anti-oxidant properties, so I wanted to continue that one.
J is currently taking Kalydeco, 1800mg of Curcumin and 75mg of Genistein per day (in applesauce). On top of that he drinks 3 glasses of organic soy milk per day (200ml each). We noticed something in his stools: some days he'd have "floaters", other days he'd have "sinkers" ("floaters" float on the water in the toilet, "sinkers" sink to the bottom. Fat in the stool makes them float.). He'd never had "floaters" before so we wondered what was going on. He was supposed to get 2 glasses of soy milk per day. As it turned out (it took a few months to figure this one out), my husband sometimes skipped a soy milk and brought a juice box on their way out to sports training. He didn't connect it to the floating stools and never told me. Till one day he said it out loud, just before heading out the door and I realised what had been happening all these months. One glass of milk caused "floaters", two glasses gave "sinkers". Simple as that. Changing back to 2 glasses every day, we noticed no more "floaters", only "sinkers". Realizing the difference a glass of soy milk can make, he now gets 3 glasses a day. Note: soy milk of course contains Genistein, that's what kept him healthy as a baby (see page 'why I started Curcumin and Genistein in the first place'). Maybe an extra capsule of Genistein per day would give the same results, maybe not. I don't know. What we are doing now is working for us, so we'll stick to that for now.

A month after starting Kalydeco, J's lung function went up by 10%. And it has been going up ever since! He's at 103% now (Oct 2016).
No one had ever told me, but apparently his small airways had started to slowly deteriorate/close up. There was talk of starting Pulmozyme (beginning of 2016), but it didn't feel right to me yet. Now (Oct 2016) his small airways are also showing improvements, so no more talk of Pulmozyme!

All the rest that we do has stayed the same (see page 'what else do we do/use' at top right hand side of this blog). He does do more sports than ever. He runs 2 or 3 times a week, 5K, interval or a full hour run (!) This summer we went swimming for an hour every day and he now does kick-boxing twice a week as well. His endurance is through the roof! Very remarkable and so extraordinary compared to other kids his age that I wonder if it has anything to do with Kalydeco.

But.... one thing I'm not happy with yet is the odds for acquiring bacterial lung infections. The odds for acquiring PA (Pseudomonas Aeruginosa) have gone down with Kalydeco, but not for any of the other bacterial infections (see this article: Pseudomonas Aeruginosa in Cystic Fibrosis Patients with G551D-CFTR Treated with Ivacaftor, Heltshe et al, 2015). A high sweat chloride concentration (SCC) won't kill you, a bacterial infection however will. So what are we missing? Everyone is looking at chloride current. Should they be looking at something else as well? I'm thinking about bicarbonate.

Something I noticed in J: every time we would go up on the CurcGen dose, J's stools would firm up. So when we started Kalydeco I had a few boxes of Macrogol (stool softener medication) on stand-by. To my huge surprise, nothing happened. Stools stayed exactly the same. So clearly Curcumin and Genistein combined does something in the intestine that Kalydeco doesn't.
CFTR doesn't just transport Chloride. It transports other things as well, like Bicarbonate, Glutathion and possibly Thiocyanate.
Bicarbonate is known to be able to thin mucus in the lungs and increased bicarbonate secretion in the intestines would explain why stools get firmer. Bicarbonate can increase pH in the lung, a very important factor in bacterial killing. Low pH (an acidic environment) decreases the bacterial killing properties of mucus. The higher the pH (more alkaline), the more bacterial killing increases. Remember I wrote that we were able to eradicate PA in J after he cultured it for a year and a half. That was quite extraordinary. Could increased bicarbonate secretion have had something to do with it? Maybe Kalydeco works really well on chloride currents and CurcGen more on bicarbonate? and glutathion?

From what I've heard, measuring bicarbonate current in CFTR proteins is really hard to do in the lab. But for me as a mom of a child with CF, that is no excuse to not do it. This is very very important for people with CF, because, as I said, bacterial infections are life-threatening, high sweat chloride concentration by itself isn't.
Apparently measuring glutathion and/or possibly thiocyanate is at the moment not possible, because there are no machines to do the measurements (said the Vertex representative). So I commented: "develop one!" "You have the budget, get in touch with a technical university and start developing a machine that can measure it!" If you have a problem, find ways to solve it! Don't just stand there.... (I didn't say that last part, but I was thinking it)



Preliminary results of the Curcumin Genistein trial

This was a trial done in 15 patients with the S1251N mutation, most of them had delf508 on the other allele. They took Curcumin and Genistein capsules 4 times a day with a meal for 2 months.
What I can share for now is that Sweat Chloride Concentration (SCC) showed a small but statistically significant drop!!!! YAY!!!
No statistically significant change in FEV1, BUT a statistically significant drop in Airway Resistance!

The drop in SCC is a lot smaller than I expected (than we all expected). In no way does it compare to the 59mmol/L drop that J has had, but at least it's statistically significant, meaning scientifically we can say Curcumin and Genistein combined works 'in vivo' on restoring defective CFTR and increasing chloride currents in the sweat glands in people with CF with the S1251N gating mutation.

Why the difference between J's results and the trial participants'? I can only hypothesize on that. We dissolved in hot soy milk (heat increases absorption for Curcumin) or mixed it through applesauce, in the trial they used capsules. The dose in the trial was higher than our dose, they started at the high dose on day 1, where we have eased into it over the years. The trial was 2 months, we've done it for 7 years. We give many other supplements (see 'what else do we do/use') and we give soy milk. Maybe it has nothing to do with any of the above and J is just the best responder to this 'treatment' (there is always a best responder...)
I hope to go back to the highest dose for a while and do a blood test to compare the results to those of the other participants.
In the meantime I'm keeping my ears and eyes open and I'm always wondering about why some people with double delF508 mutations notice improvements on Curcumin and Genistein. I have a feeling it has something to do with modifier genes and/or alternative bicarbonate channels, but I'll have to wait and see where science will take us on this.

Please see the top right hand side for links to other pages or click here:
Our story
Why I started Curcumin and Genistein in the first place
How to start?
What to expect?
Early results
What else do we do/use?
CFTR and Genistein
Curcumin general info

All feedback is highly appreciated! Please send an e-mail to curcumingenistein@yahoo.com